WO2007049121A1 - Crystal form of sodium; (3r,5r)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate - Google Patents

Abstract

A crystal form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluoropheynl)-5-isopropyl- imidazol-1-yl]-3,5-dihydroxy-heptanoate is provided.

Description

CRYSTAL FORM OF SODIUM; (3R,5R)-7-[4-BENZYLCARBAMOYL-2-(4-FLUOROPHENYL)-5- ISOPROPYL-IMIDAZOL-I -YL]-S₁S-DIHYDROXY-HEPTANOATE

BACKGROUND OF THE INVENTION

High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C)₁ in man. (cf. M.S. Brown and J. L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981)). It has been established that lowering LDL-C levels affords protection from coronary heart disease (cf . Journal of the American Medical Association, 251 , No. 3, 351 - 374 (1984)).

Statins are collectively lipid lowering agents. Representative statins include atorvastatin, lovastatin, pravastatin, simvastatin and rosuvastatin. Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. A number of patents have issued disclosing atorvastatin. These include: United States Patent Numbers 4,681 ,893; 5,273,995 and 5,969,156,\vhich are incorporated herein by reference.

All statins interfere, to varying degrees, with the conversion of HMG-CoA to the cholesterol precursor mevalonate by HMG-CoA reductase. These drugs share many features, but also exhibit differences in pharmacologic attributes that may contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary heart disease. (Clin. Cardiol. BoI. 26 (Suppl. Ill), I1I-32-III-38 (2003)). Some of the desirable pharmacologic features with statin therapy include potent reversible inhibition of HMG-CoA reductase, the ability to produce large reductions in LDL-C and non- high-density lipoprotein cholesterol (non-HDL-C), the ability to increase HDL cholesterol (HDL-C), tissue selectivity, optimal pharmacokinetics, availability of once a day dosing and a low potential for drug-drug interactions. Also desirable is the ability to lower circulating very-low-density- lipoprotein(VLDL) as well as the ability to lower triglyceride levels.

At the present time, the most potent statins display in vitro IC₅₀ values, using purified human HMG-CoA reductase catalytic domain preparations, of between about 5.4 and about 8.0 nM. (Am. J.

Cardiol. 2001; 87(suppl): 28B-32B; Atheroscer Suppl. 2002;2:33-37). Generally, the most potent LDL-C- lowering statins are also the most potent non-HDL-C-lowering statins. Thus, maximum inhibitory activity is desirable. With respect to HDL-C, the known statins generally produce only modest increases in HDL-

C. Therefore, the ability to effect greater increases in HDL-C would be advantageous as well. With respect to tissue selectivity, differences among statins in relative lipophilicity or hydrophilicity may influence drug kinetics and tissue selectivity. Relatively hydrophilic drugs may exhibit reduced access to nonhepatic cells as a result of low passive diffusion and increased relative hepatic cell uptake through selective organic ion transport. In addition, the relative water solubility of a drug may reduce the need for extensive cytochrome P450 (CYP) enzyme metabolism. Many drugs, including the known statins, are metabolized by the CYP3A4 enzyme system. {Arch. Intern. Med. 2000; 160:2273-2280; J. Am. Pharm. Assoc. 2000; 40:637-644). Thus, relative hydrophilicity is desirable with statin therapy. Two important pharmacokinetic variables for statins are bioavailability and elimination half-life. It would be advantageous to have a statin with limited systemic availability so as to minimize any potential risk of systemic adverse effects, while at the same time having enough systemic availability so that any pleiotropic effects can be observed in the vasculature with statin treatment. These pleiotropic effects include improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, reduction in blood plasma levels of certain markers of inflammation such as C-reactive protein, decreasing oxidative stress and reducing vascular inflammation. (Arterioscler. Thromb. Vase. Biol. 2001; 21 :1712-1719; Heart Dis. 5(1 ):2-7, 2003). Further, it would be advantageous to have a statin with a long enough elimination half-life to maximize effectiveness for lowering LDL-C.

Finally, it would be advantageous to have a statin that is either not metabolized or minimally metabolized by the CYP 3A4 systems so as to minimize any potential risk of drug-drug interactions when statins are given in combination with other drugs.

Accordingly, it would be most beneficial to provide a statin having a combination of desirable properties including high potency in inhibiting HMG-CoA reductase, the ability to produce large reductions in LDL-C and non-high density lipoprotein cholesterol, the ability to increase HDL cholesterol, selectivity of effect or uptake in hepatic cells, optimal systemic bioavailability, prolonged elimination half-life, and absence or minimal metabolism via the CYP3A4 system.

In addition, compounds exhibiting optimal solubility and hygroscopicity properties are desirable for pharmaceutical applications. More specifically, compounds having high aqueous solubility and low hygroscopicity in combination with high physical and chemical stability would be most beneficial for use in pharmaceutical formulations.

Sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyI-imidazol-1-yI]-3,5- dihydroxy-heptanoate, methods of making, methods of formulating and methods of using same are disclosed in U.S. Serial No. 11/105,288, which is fully incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention provides a crystalline form, "form A", of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an x-ray powder diffraction containing the following 2Θ values measured using CuKoc radiation: 7.1 , 8.6, 9.8, 10.4, 14.1 , 15.0, and 19.5. Crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluoropheynl)-5- isopropyI-imidazol-1-yl]-3,5-dihydroxy-heptanoate exhibits high water solubility, non-hygroscopicity, non- hydration, and high physical/chemical stability. Accordingly, crystalline form A of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluoropheynl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate is particularly useful for pharmaceutical formulation and application. As an inhibitor of HMG-CoA reductase, the novel crystalline form of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate described herein is a useful hypolipidemic and hypocholesterolemic agent as well as an agent in the treatment of osteoporosis and Alzheimer's disease. A further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for the production of crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyI-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy- heptanoate in unit dosage form in the treatment methods mentioned above.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further described by the following non-limiting examples which refer to the accompanying FIGS. 1 to 5, short particulars of which are given below.

FIG. 1 Powder x-ray diffractogram of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2- (4-fluorophenyl)-5~isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate.

FIG. 2 Simulated powder x-ray diffractogram of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dlhydroxy-heptanoate generated from single crystal structure.

FIG. 3 Solid-state ¹³C nuclear magnetic resonance spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate with spinning side bands identified by an asterisk. FIG. 4 Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4- fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.

FIG. 5 Solid-state ¹⁹F nuclear magnetic resonance spectrum of crystal form A of sodium; (3R,5R)-7-t4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate with spinning side bands identified by an asterisk.

DETAILED DESCRIPTION OF THE INVENTION

A crystalline form of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl- imidazol-1-yl]-3,5-dihydroxy-heptanoate, "form A", has been characterized by powder x-ray diffractometry, single-crystal x-ray diffractometry, ¹³C solid-state nuclear magnetic resonance spectroscopy, Raman spectroscopy, and ¹⁹F solid-state nuclear magnetic resonance spectroscopy. Powder X-ray Diffractometry

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl-imidazol- 1-yl]-3,5-dihydroxy-heptanoate was characterized by x-ray powder diffractometry. The x-ray powder diffraction pattern was collected on a Rigaku Ultima-plus X-ray powder diffractometer using Cu Ka radiation (1.54 A). The tube voltage and amperage were set to 4OkV and 40 mA, respectively. The sample was scanned from 3° to 50° 2-theta at a step size of 0.04° 2-theta and at 2.4 seconds per step. The diffractometer was calibrated for peak positions in 2-theta using a silicon standard. The sample was analyzed in an ASC-6 silicon sample holder purchased from Gem Dugout [State College, PA]. The analysis was conducted at room temperature, which is generally 2O⁰C to 30⁰C. Data were collected and integrated using RigMeas software version 2.8. Diffractograms were evaluated using DiffracPlus software, release 2003, with Eva version 8.0.

To perform an X-ray diffraction measurement on a Rigaku Ultima-plus X-ray powder diffractometer used for the measurement reported herein, the sample is typically placed into a cavity in the middle of the silicon sample holder. The sample powder is pressed by a glass slide or equivalent to ensure a random surface and proper sample height. The sample holder is then placed into the Rigaku Ultima-plus instrument and the powder x-ray diffraction pattern is collected using the instrumental parameters specified above. Measurement differences associated with such X-ray powder diffraction analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration errors, (d) operator errors (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation errors). Calibration errors and sample height errors often result in a shift of all the peaks in the same direction. Small differences in sample height when using a flat holder will lead to large displacements in x-ray powder diffraction peak positions. A systematic study showed that a sample height difference of 1 mm could lead to peak shifts as high as 1 °2Θ (Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001 ; 26, 63). These shifts can be identified from the X-ray diffractogram and can be eliminated by compensating for the shift (applying a systematic correction factor to all peak position values) or recalibrating the instrument. As mentioned above, it is possible to rectify differences in measurements from the various instruments by applying a systematic correction factor to bring the peak positions into agreement. In general, this correction factor will bring the measured peak positions into agreement with the expected peak positions and may be in the range of the expected 2-theta value ± 0.1 ° 2-theta.

Figure 1 shows the x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate. Table 1 lists peak positions in degrees 2-theta and relative intensities (>14%) for the x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5- dihydroxy-heptanoate. The error for the peak positions in Table 1 is expected to be about +/- 0.1 degrees 2-theta. The relative intensities are expected to vary from sample to sample depending on the experimental conditions and preferred orientation. TABLE 1

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yI]-3,5- dihydroxy-heptanoate x-ray powder diffraction pattern expressed in terms of the degrees 2-theta and relative intensities of >14% measured on a Rigaku Ultima-plus diffractometer with CuK_α radiation

Single Crystal X-ray Diffractometry

The single crystal structure of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4- fluorophenyi)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate was solved from a crystal grown from

2-propanol/water. The data were collected at room temperature (2O⁰C to 3O⁰C) using an APEX (Bruker-

AXS) diffractometer. All crystallographic calculations were facilitated by the SHELXTL software package, version 5.1. The structure was solved in the orthorhombic space group P2-|2i2-ι with Z=4 (a =5.7184(4) A, b = 18.283(3) A, c = 25.280(4) A). The structure solution contained one (3R,5R)-7-[4-benzylcarbamoyl-2- (4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate and sodium counterion pair in the asymmetric unit. All hydrogen atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms. The final model refined to a goodness fit of 0.948 R_?=0.0739 (l>2sigma(l)) and w/?₂=0.0915 (l>2sigma(l)). The determined structure was consistent with the intended structure. The simulated x-ray powder diffraction pattern was generated from the crystal information file (cif) from the crystal structure solution using MS Modeling software suite provided by Accelrys Software (2004).

Figure 2 shows the simulated x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyi-imidazol-1-yl]-3,5-dihydroxy-heptanoate. Table 2 lists peak positions in degrees 2-theta and relative intensities (>10%) for the simulated x-ray powder diffraction pattern of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. The error for the peak positions in Table 2 is expected to be about +/- 0.1 degrees 2-theta.

TABLE 2

Crystal form A of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fluorophenyl)-5-isopropyI-imidazol-1-yl]-3,5- dihydroxy-heptanoate simulated x-ray powder diffraction pattern from single crystal x-ray structure expressed in terms of the degrees 2-theta and relative intensities of >10%.

¹³C Solid-State Nuclear Magnetic Resonance Spectroscopy

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate was characterized by ¹³C solid-state nuclear magnetic resonance spectroscopy (SS-NMR). ¹³C cross-polarization magic angle spinning (CP/MAS) NMR data were acquired at a frequency of 125.65 MHz on a 500 MHz Varian INOVA spectrometer, and externally referenced to the methyl resonance of hexamethylbenzene (17.35 ppm). The spectrometer was equipped with a 7.5 mm Chemagnetics Pencil probe. 3712 data points were acquired over a 46 kHz sweep width. 256-4096 total transients were acquired. Data were acquired using cross-polarization with a ¹H-decoupling field of 63 kHz. Spinning sidebands were suppressed using a Total Suppression of Sidebands (TOSS) pulse sequence. Samples were spun at 6 kHz. Data was acquired at room temperature, which is generally 2O⁰C to 3O⁰C.

Figure 3 shows the solid-state ¹³C CP/MAS NMR spectra of crystal form A of sodium; (3R,5R)-7- [4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. Resonances due to spinning sidebands are marked with asterisks (*). Table 3 lists chemical shifts in ppm and relative intensities (>14%) for the ¹³C CP/MAS NMR spectrum of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. The error for the chemical shifts in Table 3 is expected to be about +/- 0.1 ppm. The relative intensities are expected to vary from sample to sample depending on the experimental conditions.

TABLE 3

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5- dihydroxy-heptanoate solid-state ¹³C nuclear magnetic resonance spectrum acquired at 125 MHz using a

CP-MAS solid-state NMR probe wherein chemical shift is expressed in parts per million (ppm).

Raman Spectroscopy

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyI-imidazol- 1-yl]-3,5-dihydroxy-heptanoate was characterized by Raman spectroscopy. The Raman spectrum was collected on a Kaiser Optical Systems Raman microscope interfaced with a Raman spectrometer. The laser source was a 300 mW diode laser operating at 785 nm, with an average power output of about 30 to

40 mW through a 5Ox, 11 mm working distance objective. The instrument was wavelength calibrated with a neon source such that the chemical shift of a silicon standard was within 1 cm^"1 of its expected value of 520.8 cm^"1. The spectrum collected represents an exposure time of 25 seconds with 3 accumulations at

4 cm^'1 resolution. The sample was prepared for analysis by placing a small amount onto a microscope slide and placing it under the microscope.

Figure 4 shows the Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate. Table 4 lists Raman shifts in cm^"1 and relative intensities (>13%) for the Raman spectrum of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yI]-3,5-dihydroxy-heptanoate. The error for the chemical shifts in Table 4 is expected to be about +/- 2 cm^'1. The relative intensities are expected to vary from sample to sample depending on the experimental conditions.

TABLE 4 Crystal form A of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5- dihydroxy-heptanoate Raman spectrum expressed in terms of the Raman shift (cm^"1) and relative intensities of >13% measured on a Kaiser Optical Systems Raman microscope with a solid-state diode laser operating at 785 nm.

¹⁹F Solid-State Nuclear Magnetic Resonance Spectroscopy Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-

1 -yl]-3,5-dihydroxy-heptanoate was characterized by ¹⁹F solid-state nuclear magnetic resonance spectroscopy (SS-NMR). Approximately 80 mg of the sample were tightly packed into a 4 mm ZrO spinner. The spectra were collected at ambient conditions on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. The sample was positioned at the magic angle and spun at 15.0 kHz. The fast spinning speed minimized the intensities of the spinning side bands. The number of scans was adjusted to obtain adequate S/N. The ¹⁹F solid state spectrum was collected using a proton decoupled magic angle spinning (MAS) experiment. The proton decoupling field of approximately 80 kHz was applied and 8 scans were collected. The recycle delay was set to 500 seconds to ensure acquisition of quantitative spectra. Proton longitudinal relaxation times (¹H T₁) were calculated based on a fluorine detected proton inversion recovery relaxation experiment. Fluorine longitudinal relaxation times (¹⁹F T₁) were calculated based on a fluorine detected fluorine inversion recovery relaxation experiment. The spectrum was referenced using an external sample of trifluoro-acetic acid (50% V/V in H₂O), setting its resonance to -76.54 ppm.

Figure 5 shows the solid-state ¹⁹F MAS NMR spectra of crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. Resonances due to spinning sidebands are marked with asterisks (*). Table 5 lists chemical shifts in ppm for the ¹⁹F MAS NMR spectrum of crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluoropheny!)-5- isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate. The error for the chemical shifts in Table 5 is expected to be about +/- 0.1 ppm.

TABLE 5 Crystal form A of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5- dihydroxy-heptanoate solid-state ¹⁹F nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million (ppm).

^aF shifts ppm

-108.5

Crystalline forms, in general, can have advantageous properties. A polymorph, hydrate, or solvate is defined by its crystal structure and properties. The crystal structure can be obtained from X-ray data or approximated from other data. The properties are determined by testing. The chemical formula and chemical structure does not describe or suggest the crystal structure of any particular polymorphic or crystalline hydrate form. One cannot ascertain any particular crystalline form from the chemical formula, nor does the chemical formula tell one how to identify any particular crystalline solid from or describe its properties. Whereas a chemical compound can exist in three states - solid, solution, and gas - crystalline solid forms exist only in the solid state. Once a chemical compound is dissolved or melted, the crystalline solid form is destroyed and no longer exists (Wells J.I., Aulton M. E. Pharmaceutics. The Science of Dosage Form Design, Reformulation, Aulton M.E. ed., Churchill Livingstone, 1988; 13:237). The new crystalline form of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl- imidazol-1-yl]-3,5-dihydroxy-heptanoate described herein has advantageous properties:

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyl-imidazoI- 1-yl]-3,5-dihydroxy-heptanoate is highly water soluble. 200 mg of sodium; (3R,5R)-7-[4-benzy!carbamoyl- 2-(4-fluorophenyI)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A readily dissolves in 0.2 mL of water.

Crystal form A of sodium; (3R,5R)-7-[4-benzyIcarbamoyl-2-(4-fIuorophenyl)-5-isopropyI-imidazol- 1-yl]-3,5-dihydoxy-heptanoate is non-hygroscopic. Sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4- fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A adsorbs less than 2 weight % water at 25 ⁰C and 90% RH as measured by dynamic water vapor sorption analysis. Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyI-imidazol-

1 -yl]-3,5-dihydroxy-heptanoate remains crystalline and does not deliquesce during long term storage at 23 ⁰C and 90% RH.

Grystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fIuorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate is anhydrous. Anhydrous forms are generally preferred as they have a lower propensity to dehydrate/transform to another solid form during processing and storage.

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1-yl]-3,5-dihydroxy-heptanoate is thermodynamically and physically stable. Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates during storage at 23 ⁰C and 90% RH. Further, crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5- isopropyl-imidazoi-1 -yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates when suspended in organic solvents or aqueous-organic solvent mixtures. Further, crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate does not transform to any more thermodynamically stable polymorphs or hydrates upon heating up to about 200 ⁰C

Crystal form A of sodium; (3R,5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol- 1 -yl]-3,5-dihydroxy-heptanoate is chemically stable. Crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate remains chemically stable during storage at 40 ⁰C and 75% RH. Further, crystal form A of sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate remains chemically stable during storage at 70 ⁰C.

The present invention provides a process for the preparation of crystalline Form A of sodium; (3R, 5R)-7-t4-benzylcarbamoyI-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate which comprises crystallizing sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1- yl]-3,5-dihydroxy-heptanoate from a solution in solvents under conditions which yield crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yi]-3,5-dihydroxy- heptanoate.

The precise conditions under which crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoy|- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate is formed may be empirically determined, and it is only possible to provide a few methods which have been found to be suitable in practice.

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneous^, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from two or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 1000 mg, preferably 1.0 mg to 200 mg, 2.5 mg to 150 mg, 5.0 to 100 mg, and from 10 mg to 80 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. '

In therapeutic use as hypolipidemic and/or hypocholesterolemic agents and agents to treat osteoporosis and Alzheimer's disease, the crystalline Forms A of sodium; (3R,5R)~7-[4-benzylcarbamoyl- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.5 mg to about 1000 mg daily. Daily dose ranges of about 1.0 mg to about 200 mg; about 2.5 mg to about 150 mg; about 5.0 to about 100 mg, and from about 10 mg to about 80 mg are preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The following non-limiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention.

EXAMPLE 1

Sodium; OR.δR^-y-r^Benzylcarbamoyl^-f^fiuorophenvD-δ-isoproDyl-imidazol-i-vπ-S.δ-dihvdroxy- heptanoate (crystalline Form A) Preparation

Make up a stock solution by dissolving amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4- fluorophenyl)-5-isopropyl-imidazol-1-yI]-3,5-dihydroxy-heptanoate (ca. 67 mg) (US 2005/0239857 or Example 3 below) in methanol (1 mL). Dispense the resulting stock solution (40 μL) into twenty-four crystallization vials. Evaporate the methanol from the vials in a vacuum oven at 60⁰C to yield an amorphous glass in the vials. Make several solutions of solvents and solvent mixtures comprising 0%,

1%, 5% and 10% water in the solvents acetonitrile, ethanol, 2-propanol, methanol, tetrahydrofuran, and acetone.

Method A

Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-

3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of 2-propanol/water (99:1) (75 μL) and heated for one hour at 60°C. The solution was then cooled to afford crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4--{luorophenyl)-5-isopropyl-imidazol-1-y!]-3,5-dihydroxy- heptanoate.

Method B

Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoy!-2-(4-fluorophenyl)-5-isopropyl-imidazo!-1-yl]- 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of ethanol/water (99:1) (75 //L) and heated for one hour at 60⁰C. The resulting solution was cooled and seeded with crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy- heptanoate obtained from Method A to afford crystalline Form A of sodium; (3R,5R)-7-[4- Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.

Method C

Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]- 3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of acetonitrile/water (99:1) (75 μL) and heated for one hour at 60⁰C. The resulting solution was cooled and seeded with crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yI]-3,5-dihydroxy- heptanoate obtained from Method A to afford crystalline Form A of sodium; (3R,5R)-7-[4- BenzylcarbamoyI-2-(4-fluorophenyi)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.

Method D Amorphous sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-

3,5-dihydroxy-heptanoate as prepared above was combined with a mixture of acetonitrile/water (95:5) (75 μL) and heated for one hour at 6O⁰C. The resulting solution was cooled and seeded with crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-f luorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy- heptanoate obtained from Method A to afford crystalline Form A of sodium; (3R,5R)-7-[4- BenzylcarbamoyI-2-(4-fIuorophenyl)-5-isopropyl-imidazol-1-yI]-3,5-dihydroxy-heptanoate.

Using the same methodology as provided in Methods B to D, crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate was obtained from solvent mixtures of 2-propanol (100%); 2-propanol/water (95:5) and (90:10); ethanol (100%); ethanol/water (95:5); acetonitrile (100%); acetone (100%); acetone/water (99:1); tetrahydrofuran (100%); and tetrahydrofuran/water (99:1).

Using the same methodology as provided in Methods B to D, crystalline Form A of sodium; (3R,5R)-7-[4-Benzylcarbamoyl-2-(4-fiuorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate was not observed in any solvent mixtures of methanol/water tested (100:0; 99:1; 95:5; and 90:10), nor in any of the following solvent mixtures, even after seeding with Form A crystal: ethanol/water (90:10), acetonitrile/water (90:10), acetone/water (95:5), acetone/water (90:10), tetrahydrofuran/water (95:5), and tetrahyrofuran/water (90/10).

EXAMPLE 2

Sodium: (3R,5R)-7-r4-Benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl1-3,5-dihvdroxy- heptanoate (crystalline Form A)

Step A

(Benzhvdrylideneamino)-acetic acid benzyl ester

A 3-necked, 5 L round-bottomed flask was equipped with a mechanical stirrer, a J-KEM temperature probe, and a N₂ inlet adapter connected to a bubbler. The round-bottomed flask was charged with glycine benzyl ester hydrochloride (505.2 g, 2.51 mol, 1.0 equiv.) and CH₂CI₂ (3.0 L). The milky, white reaction mixture was treated with benzophenone imine (471.1 g, 97%, 2.6 mol, 1.00 equiv.) and an exotherm (+ 4.5 ⁰C) was observed. The reaction mixture stirred at 20 ⁰C for 3h and TLC (50% ethyl acetate/heptane) showed a trace of starting material. Additional benzophenone imine (25.0 g, 0.14 mol) was added to the reaction mixture and the mixture was stirred for 15h at 20 ⁰C. TLC confirmed reaction completion. This mixture was filtered through a short pad of Celite to remove ammonium chloride, and the filter cake was rinsed with CH₂CI₂ (1.5 L). The filtrates were concentrated in vacuo to produce a white solid that was dried in vacuo to give the desired crude product: 878.7 g (106%); ¹H- NMR(DMSOd₆): 7.53-7.25 (m, 13H), 7.12 (dd, 2H), 5.10 (s, 2H), and 4.17 (s, 2H). HPLC Purity: > 95%.

Step B 2-Amino-4-methyl-3-oxo-pentanoic acid benzyl ester hydrochloride

A 3-necked, 3 L round-bottomed flask was equipped with a magnetic stir bar, a J-KEM temperature probe, an addition funnel, and a N₂ inlet adapter connected to a bubbler. The flask was charged with potassium fert-butoxide (112.0 g, 998 mmol, 1.53 equiv) and THF (750 mL). The white suspension was cooled to -70 ⁰C and was treated with (Benzhydrylideneamino)-acetic acid benzyl ester (215.0 g, 658 mmol, 1.00 equiv.) as a solution in THF (700 ml_). The orange solution stirred for 30 min at -70 ⁰C and was then transferred via cannula into a solution of isobutyryl chloride (100.0 mL, 101 g, 947 mmol, 1.45 equiv.) in THF (200 mL) at -70 ⁰C. The addition rate was such that the reaction temperature did not warm past -50 °C. After complete addition, the reaction mixture was held at -50 "C for 1 h, and was then warmed to -30 ⁰C. At this temperature, the reaction was quenched with 3 M HCl (670 mL, 2.0 mol, 3.1 equiv.). The cold bath was removed, and the reaction mixture stirred at 20⁰C for 15 h. The reaction mixture was concentrated in vacuo to produce a yellow residue that was re-dissolved in water (400 mL). The benzophenone side-product was removed by extraction with diethyl ether (2 x 400 mL), and the aqueous layer was concentrated in vacuo to produce a light yellow residue that was concentrated twice on the rotary evaporator from methanol (2 x 500 mL) to azeotropically remove water. The resulting residue was then re-dissolved in anhydrous methanol (500 mL) and potassium chloride (KCl, -82.0 g) was removed by vacuum filtration. The light yellow filtrate was concentrated in vacuo to produce a light yellow residue (16, 143.1 g, 81%). ¹H-NMR (DMSO-d₆): 9.08 (s, 3H, NH₃Cl), 7.41-7.31 (m, 5H), 5.48 (s, 1 H), 5.26 (s, 2H), 3.05 (sept, 1 H), 1.08 (d, 3H, CH₃), and 0.90 (d, 3H, CH₃). HPLC purity: 88.2%. MS: (M-HCI)= 235. This crude residue 16 can be recrystallized from a 1 :1 wt/wt ratio of crude 16 to water to provide 16 > 99% HPLC purity.

Step C

2-(4-FluorϋbenzoylaminoV4-methyl-3-oxo-pentanoic acid benzyl ester A 4-necked, 5 L round-bottomed flask was equipped with a J-KEM temperature probe and a mechanical stirrer. The flask was charged with 2-Amino-4-methyl-3-oxo-pentanoic acid benzyl ester hydrochloride (427.8 g, 99.6% HPLC purity, 1.57 mol) and CH₂CI₂ (1.0 L). The resultant solution was cooled to 0 ⁰C and was treated with a solution of potassium carbonate (546 g, 3.95 mol, 2.51 equiv.) in deionized water (1.5 L) to produce a creamy reaction mixture. The pot temperature was kept below 5 ⁰C during the potassium carbonate addition. Then, the mixture was treated with a solution of 4-fluorobenzoyl chloride (209 mL, 276 g, 1.74 mol, 1.11 equiv.) in CH₂CI₂ (500 mL) at 0 ⁰C at a rate such that the pot temperature was kept below 5 ⁰C. TLC (50% ethyl acetate/50% hexanes) showed reaction completion after 20 min and a phase cut gave the product-containing bottom yellow organic layer. The aqueous layer was extracted with CH₂CI₂ (1 x 750 mL) and discarded. The combined organic layers were washed with 0.2 M HCI (1 x 90 mL), washed with water (1 x 2 L, deionized), dried over MgSO₄, and filtered. The yellow filtrate was concentrated in vacuo to produce a light yellow solid (583.5 g, 104 %) which was recrystallized from into a refluxing mixture of MTBE (1 L) and heptane (2.5 L) to give an solid, which was collected by filtration and washed with heptane (2 x 0.5 L). This material was dried in vacuo (35 ⁰C) for 12 h to give the desired product as an off white solid: 504.0 g, (90%); ¹H-NMR (CDCI₃): 7.86 (m, 2H), 7.41-7.10 (m, 7H), 5.59 (d, 1 H), 5.27 (dd, 2H), 3.05 (m, 1H), 1.21 (d, 3H), and 1.19 (d, 3H); ¹⁹F-NMR (CDCI₃): -107.54; Low resolution mass spectroscopy (APCI) mfz 358 [M+H]⁺.

Step D

N-(1-Benzylcarbamoyl-3-methyl-2-oxo-butyl)-4-fluorobenzamide A 4-necked, 3 L round-bottomed flask was equipped with a J-KEM temperature probe, a magnetic stirrer, a condenser connected to a bubbler via a N₂ inlet adapter, and an addition funnel. The flask was charged with 2-(4-Fluorobenzoylamino)-4-methyl-3-oxo-pentanoic acid benzyl ester (200.0 g, 0.56 mol, 1.00 equiv.) and NMP (850 mL). The resultant solution was heated to 160 °C and treated in one portion with neat benzylamine (65.0 mL, 31.48 g, 0.29 mol, 1.05 equiv.). The reaction mixture was maintained at 160 ⁰C for 3 h, TLC and HPLC (50:50 ethyl acetate/hexanes) showed desired product and very little starting material. The reaction mixture was cooled to 75 ⁰C and NMP (-600 mL) was removed by vacuum distillation. The concentrated reaction mixture was poured portionwise onto a cold brine solution (1.5 L; approximately 1:2 in ice/water) and was diluted with ethyl acetate (1 L). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (1 x 500 mL). The combined ethyl acetate filtrate was concentrated in vacuo to produce a beige solid (-284 g). ¹H-NMR still showed NMP in solid residue. The solid residue was re-dissolved in ethyl acetate (1.5 L) and washed with Vz saturated brine solution (2 x 2 L; 1 L saturated brine). The organic layer was collected and concentrated in vacuoϊo produce a light yellow solid (-254 g). ¹H-NMR showed very little NMP in crude solid. Using a mechanical stirrer, crude solid (-254 g) was recrystallized with absolute EtOH (700 mL) and deionized water (700 mL) to produce an off-white solid. The off-white solid was collected by filtration and air-dried in the hood over 15 h. The off-white solid (-400 g, wet) was re-slurried in a solution of absolute ethanol (600 mL) and deionized water (600 mL), collected by filtration, and dried in vacuo 75 ⁰C (16 h) to give the desired product as^an off-white solid: (112.3 g, 56% yield, 90% HPLC purity); ¹H-NMR (CDCI₃): 7.83 (m, 2H), 7.78, (d, 1H), 7.41-7.10 (m, 6H), 5.33 (d, 1H), 4.42 (m, 2H), 3.15 (m, 1 H), and 1.10 (m, 6H); ¹⁹F-NMR (CDCI₃): -106.95; Low resolution mass spectroscopy (APCI) m/z 357 [MH-H]⁺.

Step E r(4R,6RV6-(2-Amino-ethyl)-2,2-dimethyl-π ,31dioxan-4-yll-acetic acid tert-butyl ester A 5-gallon stainless steel reactor was charged with 250 g of Ra-Ni, ((4R,6R)-6-Cyanomethyl-2,2- dimethyl-[1 ,3]dioxan-4-yl)-acetic acid tert-butyl ester (1.0 kg, 3.71 mol), toluene (6 L), methanol (675 mL), and with 6.5M NH₃ZMeOH (800 mL). The reactor was sealed, pressure tested to 3.5 bar with N₂, and purged 3 times with 3.5 bar of N₂. The reactor was purged with H₂ to 3.5 bar three times without any agitation. After the reactor was pressurized to 3.5 bar with H₂, the reaction stirred for 2-6 h, and a small exotherm to 30 to 40 ⁰C was observed. Stirring was continued until H₂ uptake ceased, then the reaction mixture was stirred at 30 to 40 ⁰C for a further 30 min. The mixture was cooled to 20 to 25 ⁰C, the H₂ source and the agitator were switched off, and the H₂ was vented from the reactor. The agitator was switched on and the stainless steel reactor was purged with N₂ to 3.5 bar 3 times. Spent Ni catalyst was filtered under a bed of nitrogen, and the stainless steel reactor and spent catalyst bed were washed with toluene (250 mL). The combined filtrates were concentrated to an approximate volume of 500 mL at a maximum temperature of 55 ⁰C under vacuum. [Note: the vacuum was broken with nitrogen]. A saturated sodium chloride solution was added and stirred for 10 minutes under nitrogen. The agitation was stopped and the phases were separated. The lower aqueous layer was discarded, and the organic layer was concentrated to produce the desired product as a yellow oil: (1.054 kg, 104%, -7% residual toluene); ¹H-NMR (400 MHz, CDCI₃): 4.23-4.19 (m, 1H), 3.99-3.95 (m, 1 H), 2.74 (t, J=7.1 Hz, 2H), 2.40- 2.36 (m, 1H), 2.27-2.22 (m, 1H), 1.58-1.41 (m, 2H), 1.40 (s, 9H), 1.31 (s, 6H), 0.89 (s, 9H); Low resolution mass spectroscopy (APCI) m/z 273 [M+Hf.

Step F

2-(4-Fluoro-phenvπ-1-r2-((2R.4R)-4-hvdroxy-6-oxo-tetrahvdro-pyran-2-yl)-Θthvπ-5-isoDropyl-1H-imidazole- 4-carboxylic acid benzylamide

To a 2-L 3-necked, round-bottomed flask outfitted with a mechanical stirrer, a J-KEM/heating mantle setup, and a Dean-Stark trap (with condenser) was charged a mixture of Λ/-(1-Benzylcarbamoyl-3- methyl-2-oxo-butyl)-4-fluorobenzamide (123.0 g, 345.1 mmol), benzoic acid (63.0 g, 517.5 mmol, 1.5 equiv.), and heptane (700 mL). This slurry was treated with [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl- [1 ,3]dioxan-4-yl]-acetic acid tert-butyl ester (119.4 g, 414.0 mmol, 1.2 equiv.). The reactor was purged with nitrogen, then heated to reflux (approximately 99 °C) over 14 h in order to azeotropically remove the water formed during the reaction. After 14 h, a small amount of starting material remained by TLC (1 :1 ^" heptane:ethyl acetate). A small portion of TBIA (5.0 g, 18.0 mmol, 0.06 equiv) was added to the reactor, and the mixture was stirred at reflux for another 2 h, after which time TLC showed no more starting material remaining. The reactor was cooled to 30 ⁰C, and the contents were fully dissolved with ethyl acetate (600 mL), washed with saturated sodium bicarbonate solution (2 x 400 mL), washed with 10% aqueous sodium chloride, then concentrated in vacuo to provide 400.1 g of a very thick orange oily solid. This solid was taken up into MeOH (600 mL) while heating to 40 ⁰C (difficult to dissolve). The solution was charged with a premixed solution of concentrated HCI (136 g) in water (400 mL), and the remaining solution was heated back to 40 ⁰C and held at this temperature for over 2 h. The walls of the reactor were washed down with MeOH (20 mL) and TLC after an additional 1 h showed mainly diol terf-butyl ester. To the reaction mixture was added MTBE (500 mL), followed by slow addition (-10 min) of a pre-mixed solution of NaOH (110 g) in water (200 mL). The pH of the mixture at this point was 13.0, and the pot temperature rose to almost 50 ⁰C. The reaction was stirred and slowly cooled to 23 ⁰C over 2 h, after which time TLC (6:1 ethyl acetate:heptane) showed that all fert-butyl ester was consumed (only baseline remaining). The mixture was diluted with more MTBE (1 L) and water (500 mL), and was phase separated. The bottom aqueous product-containing layer was extracted again with MTBE (500 mL) and set aside. The combined MTBE layers were vigorously washed with 5% NaOH solution (200 mL), then discarded. The combined aqueous extracts were combined and distilled down to approximately 1/2 volume on the rotary evaporator using full vacuum at 70⁰C (CAUTION! Severe bumping was possible; use large round-bottom flask and a bump-trap for this concentration). The mixture was then stirred at 23 ⁰C and treated with 6N HCI (200 mL, added over 1 min), at which point the mixture turned cloudy. The pH of this suspension was 7.0 (pH was measured with pH meter). To this mixture was added ethyl acetate (800 mL), and the mixture was stirred vigorously. The mixture was then treated with 6N HCI until pH of the aqueous layer (phase-cut; lower layer) was 5.5. In total, additional 6N HCI (75 mL) was added to achieve this pH. The layers were separated and the top organic layer was set aside. The aqueous layer was extracted with ethyl acetate (200 ml_) and then discarded. The combined organics were washed with water and then concentrated in vacuo to give 175 g of an orange oil that foamed slightly under vacuum. To this mixture was added 1% HCI (1 ml.) and toluene (900 mL), and the reaction mixture was heated to reflux under a Dean-Stark trap for 2.5 h [Note: Not completely in solution until near reflux]. TLC showed clean conversion to lactone. The reaction mixture was cooled to 30 ⁰C, and toluene was removed by rotary evaporator to give 171 g of a brown oil that solidified while under vacuum for 2 h. This solid was taken up in dichloromethane (60 mL) and the solution was added to the top of a 900 g silica gel column that was pre-packed in 4:1 ethyl acetate/heptane. A solution of 4:1 ethyl acetate/heptane (4 L) eluted initially a purple impurity of high R_f (0.8), followed by elution of lactone cleanly by ramping eventually to neat ethyl acetate over another 12 L. Additional ethyl acetate (6 L) was charged until the product was completely eluted as indicated by TLC (5:1 ethyl acetate/heptane). Fractions 3-6 (500 mL each) contained the purple impurity, and fractions 10-22 were combined and concentrated to afford 103.5 g of a dark grey oil that formed a tan foamy residue while drying under vacuum. NMR of this residue showed contamination with benzoic acid, so this crude product was re-dissolved in ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (2 x 200 mL), followed by washing with 100 mL water. The organic solvent was concentrated in vacuo to yield the desired product as a pale tan foamy amorphous solid: (88.4 g 53% over 4 combined steps); ¹H-NMR (CDCI₃): 7.61 (m, 2H), 7.34-7.22 (m, 7H), 4.57 (m, 1H), 4.51 (s, 2H), 4.31 (m, 1H), 4.20 (m, 2H), 3.29 (p, 1H), 2.62 (dd, 1H), 2.44 (dd, 1H), 1.90 (m, 2H), 1.71 (m, 2H), and 1.43 (d, 6H); ¹⁹F-NMR (CDCI₃): -113.66; Low resolution mass spectroscopy (APCl) m/z.480 [M+H I]1⁺+

Step G

A 3-necked, 3-L round-bottomed flask was outfitted with a large (40OmL) Dean-Stark trap (with a condenser) and a J-KEM temperature probe was charged with 2-(4-Fluoro-phenyl)-1 -[2-((2R,4R)-4- hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-5-isopropyl-1 H-imidazole-4-carboxylic acid benzylamide_(88.4 g, 184 mmol) and 1M NaOH (180.3 mL, 180.3 mmol, 0.98 equiv, based on HPLC purity of lactone 23, 98% purity in this case). The resulting mixture was diluted with water (750 mL) and warmed to 60 ^CC for 2h to aid in dissolution/conversion of lactone to sodium salt . After 2h, TLC (100% ethyl acetate) showed nearly complete consumption of lactone (R_f = 0.5). The biphasic solution was heated to reflux (~95 ⁰C) to azeotrope off water (~700 mL, some water loss through top of condenser) over 3h. The remaining white slurry was diluted with toluene (500 mL) and concentrated in vacuo to produce a beige residue (-110 g). The crude residue was transferred to the vacuum oven at 80 ⁰C for 12 h under a nitrogen sweep to afford a white solid (92.2 g). In a wide-mouth 2-L Erlenmeyer flask with a gentle nitrogen sweep, this solid was dissolved in refluxing MeOH (900 mL) with vigorous stirring. The solution was concentrated down by boiling off methanol until approximately 800 mL of total volume remained. While refluxing, 2-propanol (500 mL) was added dropwise over 60 min (so that the total volume remains -800 mL; i.e. as methanol continued to boil off, 2-propanol was added at the same rate to keep a constant reaction mixture volume), during which time the refluxing solution began to precipitate sodium salt. After full addition, the mixture was refluxed until the total volume reached 700 mL, after which heating was discontinued (stirring continued), and the slurry was cooled to 23 ⁰C (uncontrolled, no temperature ramp was used). The bright, white fluffy solid was filtered on a glass fritted filter funnel, and the cake was rinsed with 2-propanol (100 mL). The cake was sucked dry under a nitrogen sweep for 0.5 h to provide 135 g of wet cake that was placed in the vacuum oven at 75 ⁰C for 12 h under a slight nitrogen purge to afford 67.7 g of a white, fluffy solid. ¹H-NMR (CD₃OD): δ ppm 1.48 (m, 7 H), 1.58 (m, 1 H), 1.70 (m, 1 H), 1.81 (m, 1 H), 2.23 (dd, JM 5.04, 7.42 Hz, 1 H), 2.29 (dd, JM 5.24, 5.47 Hz, 1 H), 3.46 (m, 1 H), 3.73 (m, 1 H), 4.11-3.92 (m, 2 H), 4.21 (ddd, J=14.85, 11.33, 5.08 Hz, 1 H), 4.51 (s, 2 H), 7.33-7.19 (m, 7 H), 7.62 (m, 2 H); ¹⁹F-NMR (CD₃OD): -113.83; Low resolution mass spectroscopy (APCl) mfz 498 [M+H]⁺; Anal, calculated ^r C₂₇H₃₁FiN₃Na₁O₅: C, 62.42; H, 6.01; N, 8.09; Na, 4.40. Found: C, 62.32; H, 5.93; N, 8.05; Na, 4.39; IR(neat) v_max= 1657, 1574, 1512, 1411, 1223, 846, and 700 cm^"1.

EXAMPLE 3

Amorphous sodium: (3R.5R)-7-r4-Benzylcarbamov[-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-vπ-3,5- dihvdroxy-heptanoate

To a solution of reactant (A) (US 2005/0239857) in THF (100 mL) was added dropwise 1N NaOH (1 equiv. 28.15 mL, 28.15 mmole) at ambient temperature. The reaction was complete within 2 hours as no starting material was observed. The reaction mixture was concentrated under reduced pressure, and rediluted with 25 mL of distilled water. The solution was freezed and lyophilized over 16 h to give a white solid (B) (14.48 g).

Claims

CLAIMSWhat is claimed is:

1. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyI- imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an X-ray powder diffraction pattern containing at least one of the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 7.1 or 19.5.

2. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-f!uorophenyl)-5-isopropyl- imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an X-ray powder diffraction pattern containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 7.1, 15.0, and 19.5.

3. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl- imidazol-1 -yi]-3,5-dihydroxy-heptanoate having an x-ray powder diffraction pattern containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 7.1, 8.6, 9.8, 10.4, 14.1 , 15.0, and 19.5.

4. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl- imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an x-ray powder diffraction pattern according to claim 2 further comprising the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 22.2, 23.3, 24.7, 25.3, and 25.7.

5. A crystalline form A of sodium; (3R, 5R)-7-[4-benzyIcarbamoyI-2-(4-fluorophenyl)-5-isopropyl- imidazol-1 -yl]-3,5-dihydroxy-heptanoate having an x-ray powder diffraction pattern according to claim 3 further comprising the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 22.2, 23.3, 24.7, 25.3, and 25.7.

6. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl- imidazol-1 -yl]-3,5-dihydroxy-heptanoate characterized by solid state ¹³C nuclear magnetic resonance referenced to the methyl resonance of hexamethylbenzene (17.35 ppm) having the following chemical shifts expressed in parts per million (+/- 0.1 ppm): 130.7, 143.6, and 181.1.

7. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl- imidazol-1 -yl]-3,5-dihydroxy-heptanoate characterized by solid state ¹³C nuclear magnetic resonance referenced to the methyl resonance of hexamethylbenzene (17.35 ppm) according to claim 6 further comprising the following chemical shifts in parts per million (+/- 0.1 ppm): 126.2, 128.4, and 142.3.

8. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyI)-5-isopropyl- imidazol-1-yl]-3,5-dihydroxy-heptanoatθ characterized by solid state ¹³C nuclear magnetic resonance referenced to the methyl resonance of hexamethylbenzene (17.35 ppm) according to claim 7 further comprising the following chemical shifts in parts per million (+/- 0.1 ppm): 115.9,

127.0, 130.0, 133.7, 141.1, 162.0, and 163.8.

9. A crystalline form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl- imidazol-1-yl]-3,5-dihydroxy-heptanoate characterized by solid state ¹⁹F nuclear magnetic resonance referenced to trifluoroacetic acid (50% V/V in H₂O) (-76.54 ppm) comprising the following chemical shift in parts per million (+/- 0.1 ppm): -108.5.

10. A pharmaceutical composition comprising a compound according to any of claims 1 to 9 in unit dosage form and a pharmaceutically acceptable carrier.

11. A process for the preparation of crystalline Form A of sodium; (3R, 5R)-7-[4-benzylcarbamoyl-2- (4-fluorophenyl)-5-isopropyl-imidazol-1-y)]-3,5-dihydroxy-heptanoate having an X-ray powder diffraction containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 7.1, 15.0, and 19.5 which comprises crystallizing sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1 -yl]-3,5-dihydroxy-heptanoate from a solution in solvents under conditions which yield said crystalline Form A of sodium; (3R, 5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate.

12. A process according to claim 10 wherein said solvent is the following solvent or solvent mixture: 2-propanol, 2-propanol/water, ethanol, ethanol/water, acetonitrile, acetonitrile/water, acetone, acetone/water, tetrahydrofuran, or tetrahydrofuran/water.